Neuromuscular disorders in icu

NEUROMUSCULAR DISORDERS IN
ICU
DR.KALADHAR.S
FELLOW
CRITICAL CARE
CARE HOSPITAL

INTRODUCTION
• Motor weakness in a patient in the ICU may be related to
1. pre existing neuromuscular disorder
2. new onset or previously undiagnosed neuromuscular disorder
3. complications of non neuromuscular critical illness

• Whatever the cause, ICU admission related to such conditions
generally results from respiratory muscle weakness and difficulty in
swallowing with consequent aspiration.
• Early recognition and intervention is crucial; death can result from
ventilatory failure and aspiration pneumonia and the autonomic
instability which complicates some conditions.
• Neuromuscular disorders can also complicate critical illness,
increasing the duration of mechanical ventilation and of ICU and
hospital stay and causing post discharge morbidity and mortality.

• Guillain–Barré syndrome (GBS) was described by Guillain, Barré, and Strohl
in 1916 as an acute flaccid paralysis with areflexia and elevated spinal fluid
protein without pleocytosis.
• GBS has been viewed as an acute inflammatory demyelinating
polyradiculoneuropathy (AIDP) affecting nerve roots and cranial and
peripheral nerves of unknown cause that occurs at all ages.
• Over the years, it has become clear that the condition may be fatal because
of respiratory failure and autonomic nervous system abnormalities.
• It is, therefore, recognized as a potential medical and neurologic emergency
that may require the use of intensive care units (ICUs) experienced in
handling the complications of the illness.

CLINICAL FEATURES IN AIDP
• GBS often occurs 2 to 4 weeks after a flu like or diarrheal illness
caused by a variety of infectious agents, including cytomegalovirus,
Epstein–Barr and herpes simplex viruses, mycoplasma, chlamydia,
and Campylobacter jejuni.
• The major feature is weakness that evolves rapidly (usually over
days) and classically has been described as ascending from legs to
arms and, in severe cases, to respiratory and bulbar muscles.

• Frequently accompanied by tingling dysesthesias in the extremities
• Facial diparesis is present in 50% of affected individuals
• Deep tendon reflexes attenuate or disappear within the first few
days of onset.
• Cutaneous sensory deficits (e.g., loss of pain and temperature
sensation) are usually relatively mild, but functions subserved by
large sensory fibers, such as deep tendon reflexes and
proprioception, are more severely affected.

• Bladder dysfuncyion may occur in severe cases but is usually
transient.
• If bladder dysfunction is a prominent feature and comes early
in the course, diagnostic possibilities other than GBS should
be considered, particularly spinal cord disease.
• The lower cranial nerves are also frequently involved, causing
bulbar weakness with difficulty handling secretions and maintaining
an airway; the diagnosis in these patients may initially be mistaken
for brainstem ischemia.

• Most patients require hospitalization, and in different series up to
30% require ventilatory assistance at some time during the illness.
• The need for mechanical ventilation is associated with more severe
weakness on admission, a rapid tempo of progression, and the
presence of facial and/or bulbar weakness during the first week of
symptoms.

• Autonomic involvement is common and may occur even in patients
whose GBS is otherwise mild.
• The usual manifestations are loss of vasomotor control with wide
fluctuation in blood pressure, postural hypotension, and cardiac
dysrhythmias.
• These features require close monitoring and management and can
be fatal.
• Pain is another common feature of GBS.

VARIANTS OF GBS
• Several subtypes of GBS are recognized, as determined primarily
by electrodiagnostic (Edx) and pathologic distinctions.
• AIDP is the most common variant.
• Additionally, there are two axonal variants, which are often clinically
severe—the acute motor axonal neuropathy (AMAN) and acute
motor sensory axonal neuropathy (AMSAN) subtypes.
• In addition, a range of limited or regional GBS syndromes are also
encountered.
• Notable among these is the Miller Fisher syndrome (MFS), which
presents as rapidly evolving ataxia and areflexia of limbs without
weakness, and ophthalmoplegia, often with pupillary paralysis

• The MFS variant accounts for 5% of all cases and is strongly
associated with antibodies to the ganglioside GQ1b.
• Other regional variants of GBS include
1. pure sensory forms
2. ophthalmoplegia with anti-GQ1b antibodies as part of severe motor-
sensory GBS
3. GBS with severe bulbar and facial paralysis, sometimes associated
with antecedent cytomegalovirus (CMV) infection and anti-GM2
antibodies
4. acute pandysautonomia

SUBTYPE FEATURES
ELECTRO
DIAGNOSIS
PATHOLOGY
Acute inflammatory
demyelinating
polyneuropathy (AIDP)
Adults affected
more than children;
90% of cases in
western world;
recovery rapid;
anti-GM1
antibodies (<50%)
Demyelinating
First attack on
Schwann cell
surface; widespread
myelin damage,
macrophage
activation, and
lymphocytic
infiltration; variable
secondary axonal
damage
Acute motor axonal
neuropathy (AMAN)
Children and young
adults; prevalent in
China and Mexico;
may be seasonal;
recovery rapid;
anti-GD1a
antibodies
Axonal
First attack at
motor nodes of
Ranvier;
macrophage
activation, few
lymphocytes,
frequent periaxonal
macrophages;
extent of axonal
damage highly
variable

SUBTYPES FEATURES
ELECTRO
DIAGNOSIS
PATHOLOGY
Acute motor
sensory axonal
neuropathy
(AMSAN)
Mostly adults;
uncommon;
recovery slow,
often incomplete;
closely related to
AMAN
Axonal
Same as AMAN, but
also affects sensory
nerves and roots;
axonal damage
usually severe
M. Fisher syndrome
(MFS)
Adults and children;
uncommon;
ophthalmoplegia,
ataxia, and
areflexia; anti-GQ1b
antibodies (90%)
Demyelinating
Few cases
examined;
resembles AIDP

DIAGNOSIS
• The most characteristic laboratory features of GBS are an abnormal
CSF profile showing albuminocytologic dissociation (elevated
protein without pleocytosis) and abnormal nerve conduction studies.
• Although the CSF profile is usually normal during the first 48 hours
after onset, by 1 week into the illness, the CSF protein is elevated in
most patients, sometimes to levels as high as 1 g per dL.
• The cell count may be slightly increased but rarely exceeds 10 cells
per μL; the cells are mononuclear in nature. When GBS occurs as a
manifestation of HIV infection or Lyme disease, the CSF white cell
count is generally increased (25 to 50 cells per μL).
• The CSF glucose is expected to be normal.

• Electrodiagnostic studies in AIDP typically disclose slowing (less
than 80% of normal) of nerve conduction velocity, most often along
proximal nerve segments, with increases in distal motor and
sensory latencies.
• The amplitude of the evoked motor responses may be reduced
because of axon loss or distal nerve conduction block, and the
responses are frequently dispersed because of differential slowing
along still conducting axons.
• Normal sural nerve and abnormal upper extremity sensory action
potential, is characteristic of early GBS.

• Except for a mild increase in the erythrocyte sedimentation rate,
hematologic studies are normal.
• Serum electrolytes may disclose hyponatremia, sometimes to a
marked degree, because of inappropriate secretion of antidiuretic
hormone caused by a disturbance of peripheral volume receptors.
• There may be evidence of previous viral or mycoplasma infection,
such as lymphopenia or atypical lymphocytes. In some cases,
evidence of recent viral infection may be sought by measuring
antibody (Ig M) titers against specific infectious agents, especially
cytomegalovirus, Epstein–Barr virus, and C. jejuni. In selected
cases, screening for HIV infection should be undertaken.

Conditions That May Mimic Guillain–
Barré Syndrome
Myasthenia gravis
Reflexes are spared
Ocular weakness predominates
Positive response to edrophonium
EMG: decremental motor response
Botulism
Predominant bulbar involvement
Descending pattern of paralysis
Autonomic abnormalities (pupils)
EMG: normal velocities, low amplitudes, incremental response
(with high-frequency repetitive nerve stimulation)
Tick paralysis
Rapid progression (1–2 d)
Tick present
Shellfish poisoning
Rapid onset (face, finger, toe numbness)
Follows consumption of mussels/clams
Toxic neuropathies EMG: usually axon loss

Organophosphorus Acute cholinergic reaction toxicity
Porphyric Neuropathy
Mental disturbance
Abdominal pain
Diphtheretic
Neuropathy
Prior pharyngitis
Slower evolution
Palatal/accommodation paralysis
Myocarditis
Poliomyelitis
Weakness, pain, and tenderness
Preserved sensation
Cerebrospinal fluid: protein and cell count elevated
Periodic Paralysis
Reflexes normal
Cranial nerves and respiration spared
Abnormal serum potassium concentration
Critical Illness
Neuropathy
Sepsis and multiorgan failure > 2 wk
EMG: axon loss

West Nile virus
neuroinvasive disease
Associated fever, meningitis, or encephalitis
Asymmetric weakness
Cerebrospinal fluid: protein and cell count elevated
Acute myopathy of
intensive care
Tetraparesis and areflexia
Follows prolonged treatment with neuromuscular-
blocking agent and corticosteroids
Trauma, status asthmaticus, and organ transplantation
associated
Clinical and EMG features of myopathy

MANAGEMENT
• Monitor respiratory parameters: VC, arterial blood gas
• Intubate if:
• VC < 12–15 mL/kg
• Oropharyngeal paresis with aspiration
• Falling vital capacity over 4–6 h
• Respiratory fatigue with VC 15 mL/kg
• Use short-acting medications to control autonomic dysfunction
• Nursing care: frequent turns to avoid pressure sores
• Place pads at elbows and fibular head to avoid compression
neuropathies
• Physical therapy
• Subcutaneous heparin

PLASMAPHERESIS
• Exchange a total of 200 mL plasma/kg body weight over 7–14 d
(40–50 mL/kg for 3–5 sessions)a
• Albumin is used as replacement solution, not fresh-frozen plasma
• During plasmapheresis, monitor BP and pulse every 30 min
• Obtain complete blood cell count (baseline and before each
exchange to calculate plasma volume)
• Obtain immunoglobulin levels before first exchange and after last
exchange; if immunoglobulin G < 200 mg/dL after last plasma
exchange, infuse 400 mg/kg IVIG

IV IG
• IV IG - 2 g/kg divided over 5 consecutive days (0.4 g/kg/d for 5
days).
• Need for a ventilator cannot be reliably predicted on the basis of
extent of weakness; however, patients who are highly likely to
require mechanical ventilation are those with rapid disease
progression, bulbar weakness, autonomic dysfunction, and bilateral
facial weakness.
• Patients must be followed carefully with measurements of maximum
inspiratory pressure and forced vital capacity until weakness has
stopped progressing so the respiratory insufficiency can be
anticipated and managed appropriately.

• Ropper and Kehne suggest intubation if any one of the following
criteria is met: mechanical ventilatory failure with reduced expiratory
VC of 12 to 15 mL per kg, oropharyngeal paresis with aspiration,
falling VC over 4 to 6 hours, or clinical signs of respiratory fatigue at
a VC of 15 mL per kg.
• Lawn et al. found the following respiratory factors to be highly
associated with progression to respiratory failure: VC less than 20
mL per kg, maximal inspiratory pressure (MIP) less than 30 cm
H2O, maximal expiratory pressure (MEP) less than 40 cm H2O, or a
reduction of more than 30% of VC, MIP, or MEP in 24 hours.
• Elective intubation may be considered in these patients at
particularly high risk for progression to respiratory failure.

• Plasmapheresis, in general, is recommended for patients who are
unable to walk unaided, who require intubation or demonstrate a
falling VC, and who have weakness of the bulbar musculature
leading to dysphagia and aspiration.
• Treatment of patients with mild GBS (i.e., those who are still
ambulatory) is beneficial; two plasma exchanges were more
beneficial than none in time to onset of motor recovery in patients
with mild GBS.
• Patients with moderate (not ambulatory) or severe (mechanically
ventilated) GBS benefited from four exchanges; those with severe
GBS did not benefit any further with the addition of two more
exchanges.

• Because of its potential for inducing hypotension, patients who
have compromise of their cardiovascular system or autonomic
dysfunction may not tolerate this procedure.
• Plasmapheresis is safe in pregnant women and children.
• Plasmapheresis is generally not used in patients who are no longer
progressing 21 days or more after the onset of GBS.
• IVIG is as effective as plasmapheresis.
• It is preferred because of its ease of administration.

• In 3% to 12% of patients given IVIG, side effects may occur that
range from minor reactions such as flulike symptoms, headache,
nausea, and malaise to more severe side effects, including
anaphylactic reactions in IgA-deficient persons, transmission of
hepatitis C, aseptic meningitis, and acute renal failure in those with
renal insufficiency.
• Absolute contraindications to IVIG are unusual. For example,
patients with IgA deficiency may be given an IgA-poor preparation
with precautions, whereas those with renal insufficiency may be
given an IVIG sucrose-poor preparation with close monitoring of
their renal status.
• Treatment is beneficial if given within 4 wks of onset of neuropathic
symptoms for plasmapheresis and within 2 wks of onset for IVIG.
• Treatment with plasmapheresis followed by IVIG is not
recommended.

• Although retreatment with the same therapy is commonly practiced,
generally with half the initial dose used, evidence-based literature is
lacking regarding the efficacy of repeat treatment.
• Oral corticosteroids delayed recovery while IV methylprednisolone
alone was not beneficial or harmful.
• Although the combination of IVIG and IV methylprednisolone (500
mg per day for 5 days) showed no significant difference over IVIG
alone unless adjusted for various factors, there is a trend toward
shortened time to independent ambulation with combination
treatment.
• Corticosteroids are not recommended in the treatment of GBS.

INTRODUCTION
• Myasthenia gravis (MG) is a neuromuscular disorder characterized
by weakness and fatigability of skeletal muscles.
• The underlying defect is a decrease in the number of available
acetylcholine receptors (AChRs) at neuromuscular junctions due to
an antibody-mediated autoimmune attack.

• Myasthenia gravis is not rare; its prevalence in Western populations
is approximately 1 in 20,000.
• Female to Male ratio is approximately 3:2, although there are two
distinct incidence peaks, with the incidence among women peaking
in the third decade and that among men in the fifth to sixth decades.
• A mild familial predisposition has been noted

CLASSIFICATION
• Subtypes of MG are classified as
1) early onset MG;<50yrs. thymic hyperplasia and females
2) late onset MG; >50yrs. thymic atrophy and mainly males
3) thymoma associated MG
4) MG with anti MuSK Abs
5) ocular MG; symptoms only affecting EOM
6) MG with no detectable AChR and MuSK Abs

CLLINICAL CLASSIFICATION
• The Myasthenia Gravis Foundation of America clinical classification
divides MG into 5 main classes and several subclasses.
• It is designed to identify subgroups of pts of MG who share distinct
clinical features or severity of disease that may indicate different
prognoses or response to therapy.
• It should not be used to measure outcome.

Class 1
1. any ocular muscle weakness
2. may have weakness of eye closure
3. all other muscle strengths are normal
Class 2
1. mild weakness affecting muscles other than ocular muscles
2. may also have ocular muscle weakness of any severity

Class 2a MG
1. predominantly affecting limb, axial muscles or both
2. may also have lesser involvement of oropharyngeal muscles
Class 2b MG
 predominantly affecting oropharyngeal, respiratory muscles or both
 may also have lesser or equal involvement of limb, axial muscles or
both

Class 3
1. moderate weakness affecting muscles other than oular muscles
2. may also have ocular muscle weaness of any severity
Class 3a MG
 predominantly affecting limb, axial muscles or both
 may also have lesser involvement of oropharyngeal muscles
Class 3b MG
both

Class 4
1. severe weakness affecting muscles other than ocular muscles
2. may also have ocular muscle weaness of any severity
Class 4a MG
 predominantly affecting limb, axial muscles or both
 may also have lesser involvement of oropharyngeal muscles
Class 4b MG
both

• Class 5
1. intubation with or without mechanical ventilation, except when
employed during postoperative management
2. the use feeding tube without intubation places the pt in class 5b

Ab binding to the AChR activates the complement cascade, resulting in the formation of membrane
attack complex (MAC) and localized destruction of the postsynaptic NMJ membrane. This ultimately
leads to a simplified, altered morphology of the
postsynaptic membrane of the NMJ of MG patients, which lacks the normal deep folds and has a
relatively flat surface.

• Abs crosslink AChR molecules
on the NMJ postsynaptic
membrane, causing
endocytosis of the cross linked
AChR molecules and their
degradation.
• This ultimately leads to
reduced number of AChR
molecules on the postsynaptic
membrane.

• Ab binding the ACh binding
sites of the AChR causes
functional block of the AChR
by interfering with binding of
ACh released at the NMJ. this
results in failure of
neuromuscular transmission.

CLINICAL FEATURES
• The cardinal features are weakness and fatigability of muscles.
• The weakness increases during repeated use (fatigue) or late in the
day, and may improve following rest or sleep.
• The distribution of muscle weakness often has a characteristic
pattern.
• The cranial muscles, particularly the lids and extraocular muscles,
are typically involved early in the course of MG; diplopia and ptosis
are common initial complaints.

• Facial weakness produces a "snarling" expression when the patient
attempts to smile. Weakness in chewing is most noticeable after
prolonged effort, as in chewing meat.
• Speech may have a nasal timbre caused by weakness of the palate,
or a dysarthric "mushy" quality due to tongue weakness.
• Difficulty in swallowing may occur as a result of weakness of the
palate, tongue, or pharynx, giving rise to nasal regurgitation or
aspiration of liquids or food.
• Bulbar weakness is especially prominent in MuSK antibody–positive
MG.

• In 85% of patients, the weakness becomes generalized, affecting
the limb muscles as well. If weakness remains restricted to the
extraocular muscles for 3 years, it is likely that it will not become
generalized, and these patients are said to have ocular MG.
• The limb weakness in MG is often proximal and may be asymmetric.
Despite the muscle weakness, deep tendon reflexes are preserved.
• If weakness of respiration becomes so severe as to require
respiratory assistance, the patient is said to be in crisis.

• Crisis refers to threatened or actual respiratory compromise in a
myasthenic patient.
• It may reflect respiratory muscle insufficiency or inability to handle
secretions and oral intake, but it is typically a combination of both.
• With currently available treatments, myasthenic crisis is not
common.
• An occasional patient presents with fulminating disease; crisis
management then coincides with initial evaluation and institution of
therapy. Otherwise, crisis may be precipitated by other illnesses,
such as influenza or other infections, or by surgery.

• Intercurrent infection is often associated with increased weakness in
the myasthenic pt.
• Any infections should be treated aggressively.
• Both hypothyroid and hyperthyroid states are often associated with
increased weakness. Again, there is an increased association
between thyrotoxicosis and myasthenia gravis.
• The manifestations of electrolyte imbalance may be enhanced in
myasthenics.

• Special consideration must be given to respiratory care of the
myasthenic.
• Incentive spirometry should be avoided, because muscular fatigue
outweighs any potential benefit, even in the postoperative patient.
• Careful attention to respiratory toilet is key and can be complicated
by cholinesterase inhibitors, which increase respiratory secretions.
Atropine may be used to minimize this effect.

• The diagnosis of myasthenia gravis is clinically suggested in
patients who present with chronic ocular, bulbar, or appendicular
weakness, variable over time, with preservation of normal sensation
and reflexes.
• Myasthenia gravis should always be considered in the differential
diagnosis of isolated ocular or bulbar weakness.
• Again, prominent muscular fatigability and temporal fluctuation are
key features of the disease.
• Normal pupils, normal sensation, and normal reflexes are to be
expected and are helpful in diagnosing MG when coincident with an
acute or subacute paralytic illness.

EDROPHONIUM TEST
• Edrophonium hydrochloride (Enlon; formerly “Tensilon”) is a fast,
short-acting parenteral cholinesterase inhibitor.
• Myasthenic weakness typically improves transiently after
administration of 4 to 10 mg (0.4 to 1.0 mL).
• The edrophonium test may be blinded, with drug or normal saline
being injected. Whether drug or placebo, a 0.2-mL test dose is given
to screen for excessive cholinergic side effects, such as cardiac
arrhythmia, gastrointestinal hyperactivity, or diaphoresis.
• The remaining 0.8 mL is given after 1 minute.
• Interpretation of the test depends on identifying and observing an
unequivocal baseline muscular deficit that can be improved
following the injection of edrophonium.
• Ptosis and ophthalmoparesis, if present, are semiquantifiable and
well suited; if respiratory compromise is present, monitoring
maximum inspiratory pressure (MIP) or vital capacity is useful.

• If there is any doubt about the positivity of the test, it should be
considered negative.
• False-positive edrophonium tests are quite rare; false negatives are
common.
• In children, the appropriate test dose is 0.03 mg per kg, one-fifth of
which may be given as a test dose.
• Neostigmine is a longer-acting parenteral cholinesterase inhibitor
that sometimes affects a more obvious clinical response. It is also
typically associated with more obvious autonomic side effects.
• The 1.5-mg test dose (0.04 mg per kg in children) should therefore
be preceded by 0.5 mg of atropine; both may be given
subcutaneously.

SEROLOGICAL TESTING
• Approximately 85% of myasthenics have detectable serum
antibodies, which bind to acetylcholine receptors.
• A normal test does not exclude the diagnosis, especially in the
patient presenting with predominantly ocular symptoms and signs.
• Among seronegative myasthenic patients, from 30% to 70% may be
found to have antibodies directed against muscle-specific tyrosine
kinase [MuSK], an enzyme that catalyzes acetylcholine receptor
aggregation in the formation of neuromuscular junctions.

• Patients who have antibodies to MuSK are often young women
(onset of symptoms before 40 years of age) with prominent bulbar
involvement and neck or respiratory muscle weakness.
• They tend to have more severe disease requiring aggressive
immunosuppressive treatment and have a higher frequency of
respiratory crisis compared to seronegative or AChR-positive
myasthenics.
• Unlike patients with antibodies to AChR, there appears to be a
correlation between MuSK antibody levels and disease severity,
with antibody levels often decreasing after various
immunosuppressive treatments except thymectomy.

• Striated muscle antibodies that react with muscle proteins titin and
ryanodine receptor have also been found, mainly in patients with
thymoma and in those with late onset myasthenia (onset of
symptoms > 50 years of age).
• Thus, they may be helpful in the detection or recurrence of
thymoma. In addition, they tend to be associated with more severe
disease, and therefore may aid in prognosis.
• Myasthenics also have an increased incidence of other
autoantibodies, including antithyroid antibodies, antiparietal cell
antibodies, and antinuclear antibodies, although routine screening
for these is not part of the diagnostic evaluation for suspected
myasthenia gravis.

ELECTROMYOGRAPHIC STUDIES
• The electromyographic hallmark of myasthenia gravis is a
decrement in the amplitude of the muscle potential seen after
exercise or slow repetitive nerve stimulation. The decrement should
be at least 10% and preferably 15% or more.
• Routine motor and sensory conduction studies are normal.
• The more severely affected patient is more likely to show a
decremental response; responses are most consistently elicited
from facial and proximal muscles.
• If a significant decrement is observed, exercising the muscle briefly
for 10 seconds transiently reverses the decrement.

• Single-fiber electromyography is relatively sensitive, documenting
increased jitter variability in the temporal coupling of single fibers
within the same motor unit. Increased jitter, however, is far from
specific; most peripheral neurogenic diseases also lead to increased
jitter.
• Muscle biopsy has no role in the evaluation of myasthenia, unless
there is a strong consideration of neurogenic or inflammatory
weakness.

GENERAL MEASURES
• When the weakening myasthenic reaches a point at which
increased respiratory effort is required, fatigue often prevents the
effective use of secondary muscles, and respiratory failure rapidly
ensues.
• FVC and MIP are better indices and should be serially charted.
• The FVC should be assessed with the patient both sitting and
supine, because diaphragmatic paresis may be accentuated in the
supine position.
• An FVC less than 20 mL per kg or an MIP greater than (i.e., not as
negative as) -40 cm H2O suggests impending failure and usually
warrants intubation.
• If a downward trend is noted (greater than 30% decrease), elective
intubation should be considered even sooner, unless there is a
realistic expectation of rapid reversal.

• The possibility of cholinergic crisis in patients receiving
anticholinesterase drugs (e.g., pyridostigmine), although no longer
common, should not be overlooked. The presence of fasciculations,
diaphoresis, or diarrhea should alert the clinician to this possibility.
• There are four basic therapies used to treat MG:
(i) symptomatic treatment with acetylcholinesterase inhibitors,
(ii) rapid short-term immunomodulating treatment with plasmapheresis
and intravenous immunoglobulin,
(iii) chronic long-term immunomodulating treatment with glucocorticoids
and other immunosuppressive drugs,
(iv) surgical treatment.

ACETYLCHOLINESTERASE INHIBITORS
• Acetylcholinesterase inhibitors are used as a symptomatic therapy
and act by increasing the amount of available acetylcholine at the
NMJ.
• They do not alter disease progression or outcome.
• Pyridostigmine is the most commonly used drug.
• It has a rapid onset of action within 15 to 30minutes reaching peak
activity in about two hours.
• The effect lasts for about three to four hours.
• The initial oral dose is 15–30 mg every 4–6 hours and is titrated
upwards depending on the patient’s response.

• Adverse side effects of Pyridostigmine are mostly due to the
cholinergic properties of the drug such as abdominal cramping,
diarrhea, increased salivation and bronchial secretions, nausea,
sweating, and bradycardia.
• Nicotinic side effects are also frequent and include muscle
fasciculation and cramping. High doses of pyridostigmine exceeding
450 mg daily, administered to patients with renal failure, have been
reported to cause worsening of muscle weakness.
• Response to treatment varies from marked improvement in some
patients to little or no improvement in others.

SHORT TERM IMMUNOMODULATING
THERAPIES
• Plasma exchange and intravenous immunoglobulin have rapid
onset of action with improvement within days, but this is a transient
effect.
• They are used in certain situations such as myasthenic crisis and
preoperatively before thymectomy or other surgical procedures.
• They can be used intermittently to maintain remission in patients
with MG who are not well controlled despite the use of chronic
immunomodulating drugs.

PLASMAPHERESIS
• It improves strength in most patients with MG by directly removing
AChRAbs from the circulation.
• Typically one exchange is done every other day for a total of four to
six times.
• Adverse effects of plasmapheresis include hypotension,
paresthesias, infections, thrombotic complications related to venous
access, and bleeding tendencies due to decreased coagulation
factors

IV IG
• It involves isolating immunoglobulins isolated from pooled human
plasma by ethanol cryoprecipitation and is administered for 5 days
at a dose of 0.4 g/kg/day, fewer infusions at higher doses are also
used.The mechanism of action of IVIg is complex.
• Factors include inhibition of cytokines competition with
autoantibodies, and inhibition of complement deposition.
• Interference with the binding of Fc receptor on macrophages, Ig
receptor on B cells, and interference with antigen recognition by
sensitized T cells are other mechanisms.
• IVIg is considered to be safe but rare cases of complications do
occur such as thrombosis due to increased blood viscosity and
other complications related to large volumes of the infused
preparation.

• More specific techniques to remove pathogenic anti-AChR
antibodies utilizing immunoadsorption have been developed
recently, which offer a more targeted approach to MG treatment.
• Clinical trials showed significant reduction of blocking antibodies
with concomitant clinical improvement in patients treated with
immunoadsorption techniques.
• Compared to plasma exchange, IVIg is similar in terms of efficacy
mortality, and complications.
• However, plasma exchange has considerable cost advantages over
IVIg with a cost benefit ratio of 2 : 1 for treatment of myasthenia
gravis.

CORTICOSTEROIDS
• Corticosteroids were the first and most commonly used
immunosuppressant medications in MG.
• Prednisone is generally used when symptoms of MG.
• Temporary exacerbation can occur after starting high doses of
prednisone within the first 7–10 days which can last for several
days.
• In cases known to have severe exacerbations, plasma exchange or
IVIg can be given before prednisone therapy to prevent or reduce
the severity of corticosteroid-induced weakness and to induce a
more rapid response.
• Oral prednisone might be more effective than anticholinesterase
drugs in oMG and should therefore be considered in all patients with
oMG.

NONSTEROIDAL IMMUNOSUPPRESSIVE
AGENTS
• Azathioprine, a purine analog, reduces nucleic acid synthesis,
thereby interfering with T-and B-cell proliferation.
• It usually takes up to 15 months to detect clinical response.
• When used in combination with prednisone, it might be more
effective and better tolerated than prednisone alone.
• Adverse side effects include hepatotoxicity and leukopenia.

• Mycophenolate mofetil selectively blocks purine synthesis, thereby
suppressing both T-cell and B-cell proliferation.
• The standard dose used in MG is 1000 mg twice daily, but doses up
to 3000 mg daily can be used.
• Higher doses are associated with myelosuppression, and complete
blood counts should be monitored at least once monthly.
• The drug is contraindicated in pregnancy and should be used with
caution in renal diseases, GI diseases, bone marrow suppression,
and elderly patients.

• Cyclophosphamide administered intravenously and orally is an
effective treatment forMG.
• More than half of the patients become asymptomatic within 1 year of
treatment.
• Undesirable side effects include hair loss, nausea, vomiting,
anorexia, and skin discoloration, which limit its use to the
management of patients who do not respond to other
immunosuppressive treatments.
• Cyclosporine blocks the synthesis of IL-2 cytokine receptors and
other proteins critical to the function of CD4+ T cells.

• Cyclosporin is used mainly in patients who do not tolerate or
respond to azathioprine.
• Large retrospective studies have supported its use as a steroid-
sparing agent.
• Tacrolimus has been used successfully to treat MG at low doses.
• It has the theoretical advantage of less nephrotoxicity than
cyclosporine.
• However, there are more controlled trial data supporting the use of
cyclosporine.Tacrolimus also has the potential for severe side
effects.

• MG patients resistant to therapy have been successfully treated with
cyclophosphamide in combination with bone marrow transplant or
with rituximab, a monoclonal antibody against the B cell surface
marker CD20.
• Etanercept, a soluble and a recombinant TNF receptor blocker, has
also been shown to have steroid-sparing effects in studies on small
groups of patients.

THYMECTOMY
• Surgical treatment is strongly recommended for patients with
thymoma.
• Thymectomy is advised as soon as the patient’s degree of
weakness is sufficiently controlled to permit surgery.
• Patients undergoing surgery are usually pretreated with low-dose
glucocorticoids and IVIg.
• Thymectomy may not be a viable therapeutic approach for anti-
MuSK antibody-positive patients because their thymi lack the
germinal centers and infiltrates of lymphocytes that characterize
thymi in patients who have anti-AChR antibodies.

• This supports a different pathologic mechanism in anti-MuSK Ab-
positive and anti-AChR Abpositive MG.
• Most experts consider thymectomy to be a therapeutic option in anti-
AChR Ab-positive gMG with disease onset before the age of 50
years.

REHABILITATION
• A rehabilitation program in combination with other forms of medical
treatment can help relieve symptoms and improve function in MG.
• Physical therapy is beneficial for long-term restoration of muscle
strength.
• Graded strengthening exercises help the individual remain as
functional as possible.
• Occupational therapy helps the individual adapt to new ways of
performing daily living tasks using energy conservation and
compensatory techniques.

NEUROMUSCULAR WEAKNESS
ACQUIRED IN THE ICU

• It is a major cause of morbidity for survivors of critical illness.
• Although reversible, ICU-acquired muscle weakness often markedly
prolongs the total duration of hospitalization and subsequent care.
• Three basic causes of acquired neuromuscular weakness in the ICU
have been identified:
(1) a sensorimotor polyneuropathy,
( 2) an acute myopathy, and
(3) persistent blockade of the neuromuscular junction

• Residual blockade of the neuromuscular junction after
discontinuation of a neuromuscular blocking agent (NMBA) is rarely
responsible for persistent neuromuscular weakness in the ICU.
• Recovery from paralysis almost always occurs within hours of
discontinuing the commonly used NMBAs, with the exception of
vecuronium administration in renal failure.
• Therefore, ICU–acquired muscle weakness is nearly always caused
by a sensorimotor polyneuropathy or by acute myopathy.
• CIM is probably the major contributor to severe ICU-acquired
weakness, while CIPN affects 70% to 80% of patients with severe
sepsis and multiorgan failure.

CIM - RISK FACTORS
• IV corticosteroids and neuromuscular blocking agents are
considered major risk factors.
• Occasionally, the myopathy develops in patients who have received
high-dose corticosteroids alone, without neuromuscular blocking
agents, or in patients who have received neither corticosteroids nor
neuromuscular blocking agents, but the latter group typically has
severe systemic illness with multiorgan failure and sepsis.

DIAGNOSIS
• The hallmark of critical illness myopathy is weakness that is typically
diffuse in distribution, affecting both limb and neck muscles.
• As is typical of most myopathic disorders, weakness tends to have a
proximal predominance in the limbs, but it may also involve distal
muscles profoundly.
• Tendon reflexes tend to be depressed but present, and on occasion,
may be absent, possibly due to a generalized reduction in
membrane excitability that occurs in sepsis.
• There may be facial muscle involvement, and rarely, extraocular
muscles are affected; other muscles supplied by cranial nerves are
usually spared.

• An elevated CK level helps to support the diagnosis of a myopathic
cause of weakness in an ICU patient, but in the myopathy of
intensive care, the CK rise, which is found in about 50% of affected
patients, only occurs early in the course of the illness, peaks within
a few days of onset, and then declines back into the normal range.
• With nerve conduction studies, motor responses are typically low-
amplitude or absent, while sensory responses are relatively
preserved, with amplitudes that are > 80% of normal in two or more
nerves (sensory responses may be reduced, however, when ICU
polyneuropathy coexists;).

• An interesting observation made of patients with CIM, and
demonstrated by direct muscle stimulation, is that the condition
leads to electrical inexcitability of the muscle membrane so that the
ratio of nerve-evoked muscle action potential to direct stimulation of
muscle is close to 1.
• In contrast, when weakness stems from severe neuropathy, the
ratio of nerve-evoked response to muscle-stimulation–evoked
response is less than 1 (and close to 0).
• Needle electrode examination shows fibrillation potential activity in
resting muscle in some patients.

• Biopsy shows muscle fiber atrophy, especially involving the type II
fibers; a variable degree of muscle fiber necrosis, the absence of
any inflammatory cells; and the hallmark of the disorder: features of
a disrupted intramyofibrillar network that manifests as patchy or
complete reduction in myosin–adenosine triphosphatase reactivity in
nonnecrotic fibers due to a loss of myosin that may be confirmed
immunocytochemically or by electron microscopy.
• With a fairly stereotypic clinical presentation, and EMG results
typical of a myopathy—often with fibrillation potential activity—the
muscle biopsy is usually not necessary to establish the diagnosis of
ICU myopathy.

PATHOPHYSIOLOGY
• Myosin loss and muscle fiber necrosis probably contribute to
persisting weakness. Myosin loss is characteristic of critical illness
myopathy, and is essentially pathognomonic of the disorder.
• Corticosteroids may cause the loss of myosin, but other factors
trigger the process, such as an abnormal neuromuscular junction
caused by pharmacologic blockade in ICU patients.
• Some patients who are not exposed to administered corticosteroids
or neuromuscular blocking agents, but who are systemically ill, often
with metabolic acidosis, can also develop the myopathy of intensive
care.

• Acidosis may stimulate glucocorticoid production, lead to an
increase in muscle protein degradation, and trigger thick filament
loss.
• Paralysis appears to be due to abnormal inactivation of sodium
channels, which suggests that the myopathy of intensive care may
be, in part, an acquired disease of ion channel gating.

TREATMENT
• Essentially symptomatic
• Treat the underlying systemic illness
• Discontinue or minimise the use of corticosteroids and NMBA.
• There is emerging evidence that intensive insulin therapy might
have a role in reducing the incidence of both critical illness
myopathy and critical illness polyneuropathy.

CIPN - DIAGNOSIS
• Patients with critical illness polyneuropathy develop a sensorimotor
axon-loss polyneuropathy.
• Although distal muscles may be affected to a greater extent than
proximal muscles, more commonly there is generalized flaccid
weakness with depressed or absent reflexes.
• There is usually distal sensory loss, but pain and paresthesias are
not typical features.
• The cranial nerves are generally spared.
• Many patients with critical illness polyneuropathy have a
concomitant encephalopathy stemming from their underlying
multiorgan system failure or sepsis, or both.

• The most important diagnostic test is the EMG.
• Nerve conduction velocities are normal or only mildly reduced, but
the amplitudes of sensory and motor responses are reduced, or
even absent.
• This pattern is typical for axon-loss polyneuropathies rather than
demyelinating neuropathies and is helpful in distinguishing CIPN
from the Guillain–Barré syndrome.
• On needle electrode examination, there are typically features of
acute denervation—fibrillation potentials and positive sharp wave
activity—and reduced recruitment of motor unit potentials; as in
many axon-loss polyneuropathies, there may be more pronounced
changes seen in distal compared to more proximal muscles.

PATHOPHYSIOLOGY
• The polyneuropathy appears to be a complication of the systemic
inflammatory response syndrome (SIRS) triggered by sepsis,
severe trauma, or burns.
• It may be induced by impaired microcirculation leading to reduced
nerve perfusion and endoneurial edema which leads in turn to nerve
hypoxia; the neuropathy may also result to a degree from the
deleterious effects of cytokines produced by activated leukocytes.
• There is also evidence that the acute polyneuropathy in critically ill
patients stems in part from an abnormality in nerve excitability,
caused by increased sodium channel inactivation (similar to what is
found in the myopathy of intensive care), without actual nerve
damage.

TREATMENT
• Essentially symptomatic and supportive.
• Stabilising the underlying illness.
• IIT may have a role.
• Recovery of sensory and motor function occurs over weeks to
months, depending on the severity of the neuropathy.
• In some of the instances of very slow recovery over months, long-
term ventilatory support may be required, even after the underlying
critical illness has resolved.

DISTINGUISHING CIM FROM CIPN
• Favoring the diagnosis of myopathy would be severe generalized
weakness, with failure to wean from mechanical ventilation (the
latter more likely to be associated with ICU myopathy rather than
neuropathy, preservation of reflexes and sensation, a transient rise
in CK, and an EMG picture of relatively preserved sensory
responses with low or absent motor responses and early
recruitment of small, polyphasic motor unit potentials, often with
fibrillation potential activity.
• Favoring a polyneuropathy would be the clinical findings of
demonstrable sensory loss and areflexia, and the EMG findings of
absent or low motor amplitudes in the company of absent or low
sensory responses, along with fibrillation potentials and reduced
recruitment of motor unit potentials. Clinically, a polyneuropathy
might easily be missed because, in many patients, careful sensory
examination is impossible in the ICU setting, especially if there is a
coexisting encephalopathy.

• It may be difficult to distinguish one disorder from another in an
individual case.
• ICU-related myopathy and polyneuropathy arise in a common
setting, share the clinical features of severe generalized weakness
with areflexia, may have a similar underlying acquired sodium
channelopathy, and cannot always be reliably differentiated by EMG
testing.
• It is likely that in many patients both disorders are present in varying
degrees and in fact have a combined syndrome of critical illness
myopathy and polyneuropathy and may be considered to have
critical illness polyneuromyopathy.

SIGNS AND SYMPTOMS OF
RESPIRATORY FAILURE
Generalised warning signs
 Increasing generalised weakness
 Dysphagia
 Dysphonia
 Dyspnea on exertion and at rest
Subjective Assessment
 Rapid shallow breathing
 Weak cough
 Tachycardia
 Staccato speech
 Accessory muscle use

 Abdominal paradox
 Orthopnea
 Weakness of trapezius and neck muscles
 Single breath count
 Cough after swallowing
Objective Assessment
 VC <15ml/kg or <1L or 50% drop in VC
 MIP > -30 cm H2O
 MEP < 40 cm H2O
 Nocturnal desaturation

• A successful approach to these disorders requires the physician to
recognize the nature of the clinical situation prompting neurologic
consultation or admission to the ICU.
• An analysis of types of neurologic clinical situations being
encountered often guides the physician initially in diagnosis and
management.

Neuromuscular disorders in icu

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